Cysteine Prodrugs

ABSTRACT

Novel cysteine prodrugs and their use in the treatment of diseases and/or conditions, including but not limited to diseases and/or conditions of the Central Nervous System (CNS), including but not limited to schizophrenia, drug craving, drug addiction, bipolar disorder, anxiety, depression, Parkinson&#39;s disease, Alzheimer&#39;s disease, cognitive dysfunction, multiple sclerosis, Amyotrophic lateral sclerosis (ALS), ischemic stroke, HIV dementia, and Huntington&#39;s disease.

FIELD OF THE INVENTION

This invention relates to novel cysteine prodrugs and methods of usingthese compounds for the treatment of diseases and/or conditions,including but not limited to diseases and/or conditions of the CentralNervous System (CNS), including but not limited to schizophrenia, drugcraving, drug addiction, bipolar disorder, anxiety, depression,Parkinson's disease, Alzheimer's disease, cognitive dysfunction,multiple sclerosis, Amyotrophic lateral sclerosis (ALS), ischemicstroke, HIV dementia, and Huntington's disease.

BACKGROUND OF THE INVENTION

Diseases and/or conditions of the Central Nervous System (CNS) affect alarge number of people. One of the CNS disorders, schizophrenia, is adebilitating disorder afflicting 1% of the world's population. Thedevelopment of effective medications to treat schizophrenia relies onadvances in characterizing the underlying pathophysiology.

Conventional approaches to treating schizophrenia and other CNSdisorders have significant disadvantages, including suboptimal efficacyand/or side effects associated with their use. For example, existingfirst and second generation antipsychotic agents have a number ofshortcomings and significant side effects, such as extrapyramidal sideeffects, endocrine effects, obesity, elevated triglycerides, bloodpressure and glucose levels, type II diabetes, cardiovascular disease,renal toxicity and agranulocytosis. Thus, it is desirable to developnovel agents that can improve treatment outcomes and safety.

Accordingly, there is a significant need for new therapeutical agents totreat disorders of the CNS.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to cysteine prodrugs ofFormulas I-VII as described below.

In another aspect, the present invention provides methods of treating adisease or condition of the Central Nervous System (CNS), including butnot limited to schizophrenia, drug craving, drug addiction, bipolardisorder, anxiety, depression, Parkinson's disease, Alzheimer's disease,cognitive dysfunction, multiple sclerosis, Amyotrophic lateral sclerosis(ALS), ischemic stroke, HIV dementia, and Huntington's diseasecomprising administering to a subject in need thereof a therapeuticallyeffective amount of any of the inventive compounds.

In some aspects, the methods and compositions of the invention may beused in combination with N-acetyl cysteine (NAC).

Thus, in one embodiment, the invention is directed to a combinationaluse of: 1) a compound of any of Formulas I-VII and 2) NAC for thetreatment of a disease or condition of CNS including but not limited toschizophrenia, drug craving, drug addiction, bipolar disorder, anxiety,depression, Parkinson's disease, Alzheimer's disease, cognitivedysfunction, multiple sclerosis, ALS, ischemic stroke, HIV dementia, andHuntington's disease.

In some aspects, the methods and compositions of the invention may beused in combination with conventional first and second generationanti-psychotic agents.

Thus, in one embodiment, the invention is directed to a combinationaluse of: 1) a compound of any of Formulas I-VII and/or NAC and 2)pre-existing first generation anti-psychotic agents (including but notlimited to chlorpromazine, thioridazine, mesoridazine, loxapine,molindone, perphenazine, thiothixene, trifluoperazine, haloperidol,fluphenazine, droperidol, zuclopenthixol andprochlorperazineperphenazine) and/or second generation anti-psychoticagents (including but not limited to amisulpride, aripiprazole,asenapine, blonanserin, clotiapine, clozapine, iloperidone, lurasidone,mosapramine, olanzapine, paliperidone, perospirone, quetiapine,remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine,bifeprunox (DU-127,090), pimavanserin (ACP-103), and vabicaserin(SCA-136)) for the treatment of a disease or condition of CNS, includingbut not limited to schizophrenia, drug craving, drug addiction, bipolardisorder, anxiety, depression, Parkinson's disease, Alzheimer's disease,cognitive dysfunction, multiple sclerosis, ALS, ischemic stroke, HIVdementia, and Huntington's disease.

Thus, in one aspect, the present invention is directed to compounds ofFormula I:

where

-   R is selected from the group consisting of alkyl and aryl,    preferably from methyl and phenyl.

In another aspect, the present invention is directed to compounds ofFormula II:

where R is selected from the group consisting of

In another aspect, the present invention is directed to compounds ofFormula III:

where R is selected from the group consisting of

where R₁ is alkyl, preferably methyl, or aryl, preferably, phenyl; or R₁comprises an amino acid with the carbonyl.

In another aspect, the present invention is directed to compounds ofFormula IV:

where R is selected from the group consisting of

In another aspect, the present invention is directed to the compoundshaving the following structures:

The invention also encompasses pharmaceutically acceptable salts,esters, stereoisomers, enantiomers, and prodrugs of the providedcompounds.

A preferred route of administering to the subject is via oral delivery.In a preferred embodiment, the disease is schizophrenia.

The invention further encompasses pharmaceutical compositions containinga compound of any of Formulas I-VII or a pharmaceutically acceptablesalt thereof in combination with a pharmaceutically acceptable carrier.

Methods of formulating/manufacturing such pharmaceutical compositionsfor the treatment of a disease or condition in a subject are also withinthe invention's scope.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are used, unless otherwise described.

The term “prodrugs” refers to compounds, including but not limited tomonomers and dimers of the compounds of the invention, which becomeunder physiological conditions compounds of the invention or the activemoieties of the compounds of the invention.

The term “active moieties” refers to compounds which arepharmaceutically active in vivo, whether or not such compounds arecompounds of the invention.

The term “alkyl” refers to a monovalent saturated aliphatic hydrocarbonincluding straight chain and branched chain groups. Preferably, thealkyl group has 1 to 20 carbon atoms. More preferably, it is a mediumalkyl (having 1 to 10 carbon atoms). Most preferably, it is a loweralkyl (having 1 to 4 carbon atoms). The alkyl group may be substitutedor unsubstituted.

The term “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkylgroup; preferably an alkoxy group refers to a lower alkoxy, and mostpreferably methoxy or ethoxy.

The term “aryl” refers to a monocyclic or bicyclic aromatic group (e.g.,phenyl or naphthyl) that can be unsubstituted or substituted, forexample, with one or more, and in particular one to three, substituents,such as halo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio,alkylsulfonyl, and alkylsulfonyl.

The term “heteroaryl” refers to a monocyclic, bicyclic, or tricyclicring system containing one, two, or three aromatic rings and containingat least one nitrogen, oxygen, or sulfur atom in an aromatic ring, andwhich can be unsubstituted or substituted, for example, with one ormore, and in particular one to three, substituents, such as halo, alkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino,alkylamino, acylamino, alkylthio, alkylsulfonyl, and alkylsulfonyl.Examples of heteroaryl groups include, but are not limited to,2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4H-carbazolyl, acridinyl,benzo[b]thienyl, benzothiazolyl, 13-carbolinyl, carbazolyl, chromenyl,cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl,imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl,isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl,naptho[2,3-b], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl,triazolyl, and xanthenyl.

The term “phenyl” refers to a cyclic group of atoms with the formulaC₆H₅ and which can be unsubstituted or substituted, for example, withone or more, and in particular one to three, substituents, such as halo,alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro,amino, alkylamino, acylamino, alkylthio, alkylsulfonyl, andalkylsulfonyl.

The term “ester” refers to compounds having a generic structure ofRCO₂R′, where R and R′ are the organic parts of the carboxylic acid andalcohol respectively.

The term “cleavable ester” refers to an ester in which the carboxylgroup has been protected by any of the known ester protective groupscapable of being removed following the acylation reaction by methods,e.g. chemical or enzymatic hydrolysis, treatment with chemical reducingagents under mild conditions, irradiation with ultraviolet light orcatalytic hydrogenation, which do not result in any appreciabledestruction of the remaining portion of the molecule. Examples ofsuitable “cleavable esters” include allyl, trialkylsilyl (e.g.trimethylsilyl) and other esters derived from silyl alcohol or stannylalcohol which can be removed by solvolysis with a solvent containinghydroxyl groups, t-butoxycarbonyl, benzhydryl, benzyl, p-nitrobenzyl,p-methoxybenzyl, 2,2,2-trichloroethyl, phenacyl, acetonyl,p-bromophenacyl, (lower)alkyl such as methyl, ethyl or t-butyl and thephysiologically hydrolyzed esters mentioned above. The general methodsfor the preparation of these esters and for their removal are describedin the literature and are well-known to those skilled in the art.

The term “thioester” refers to a compound with the functional groupC—S—CO—C.

The term “dimer” refers to the chemical entity formed by disulfidelinkage of two identical prodrugs, or protected cysteine analogsdescribed herein.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from a combination of thespecified ingredients in the specified amounts.

The term “subject” includes mammals, including humans. The terms“patient” and “subject” are used interchangeably.

In general, unless indicated otherwise, a chemical group referred toanywhere in the specification can be optionally substituted.

The term “therapeutically effective amount” means the amount of acompound that, when administered to a subject for treating a disease ordisorder, is sufficient to effect such treatment for the disease ordisorder. The “therapeutically effective amount” can vary depending onthe variety of factors, including the compound, the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

In one embodiment, the terms “treating” or “treatment” refer toameliorating the disease or disorder (i.e., arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment, “treating” or “treatment” refers toameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder, or even preventing the same.

The term “combinational use” as used in the present inventionencompasses co-formulations of the two active agents as well asco-administration of two active agents as separate formulations.

Description of the Invention

The present invention incorporates and is based on new and emergingscientific understanding of the disorders of the Central Nervous System(CNS). In particular, the present invention is based in part on theunderstanding of the importance of overcoming metabolic challengesconnected with successfully delivering effective moieties of the agentsto the CNS. In addition, the present invention is based in part on therecognition that glutamatergic dysfunction plays an important role inthe disorders of the CNS. Therefore, it is important that novel agentsbe able to modulate glutamatergic dysfunction.

In one aspect, the present invention is directed to cysteine prodrugs ofFormulas I-VII as described below.

In another aspect, the invention is directed to a method of treating adisease or condition of CNS, including but not limited to schizophrenia,drug craving, drug addiction, bipolar disorder, anxiety, depression,Parkinson's disease, Alzheimer's disease, cognitive dysfunction,multiple sclerosis, ALS, ischemic stroke, HIV dementia, and Huntington'sdisease in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound of any ofFormulas I-VII, or a pharmaceutically acceptable salt thereof.

Preferably, diseases or conditions treatable with the compounds of thepresent invention are related to CNS. In a preferred embodiment, thedisease is schizophrenia. In general, the invention is not limited totreatment of any specific disease or condition but encompasses thetreatment of any disease or condition whose mechanism may be affected bythe compounds of the present invention.

In some aspects, the methods and compositions of the invention may beused in combination with N-acetyl cysteine (NAC).

Thus, in one embodiment, the invention is directed to a combinationaluse of: 1) a compound of any of Formulas I-VII and VII) NAC for thetreatment of a disease or condition of CNS, including but not limited toschizophrenia, drug craving, drug addiction, bipolar disorder, anxiety,depression, Parkinson's disease, Alzheimer's disease, cognitivedysfunction, multiple sclerosis, ALS, ischemic stroke, HIV dementia, andHuntington's disease. In some aspects, the methods and compositions ofthe invention may be used in combination with conventional first andsecond generation anti-psychotic agents.

Thus, in one embodiment, the invention is directed to a combinationaluse of: 1) a compound of any of Formulas I-VII and/or NAC and 2)pre-existing first generation anti-psychotic agents (including but notlimited to chlorpromazine, thioridazine, mesoridazine, loxapine,molindone, perphenazine, thiothixene, trifluoperazine, haloperidol,fluphenazine, droperidol, zuclopenthixol andprochlorperazineperphenazine) and/or second generation anti-psychoticagents (including but not limited to amisulpride, aripiprazole,asenapine, blonanserin, clotiapine, clozapine, iloperidone, lurasidone,mosapramine, olanzapine, paliperidone, perospirone, quetiapine,remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine,bifeprunox (DU-127,090), pimavanserin (ACP-103), and vabicaserin(SCA-136)) for the treatment of a disease or condition of CNS, includingbut not limited to schizophrenia, drug craving, drug addiction, bipolardisorder, anxiety, depression, Parkinson's disease, Alzheimer's disease,cognitive dysfunction, multiple sclerosis, ALS, ischemic stroke, HIVdementia, and Huntington's disease.

In all described methods, compounds of the present invention, NAC andpre-existing first and second generation anti-psychotic agents are usedin therapeutically effective amounts.

In a preferred embodiment, the combinational use of the compounds of thepresent invention with NAC and/or pre-existing first and/or secondgeneration anti-psychotic agents allows to decrease the therapeuticallyamount of NAC and/or the pre-existing first and/or second generationanti-psychotic agents that would be necessary to administer withoutadministration of the compounds of the present invention.

The invention also encompasses veterinary use of the provided compoundsfor CNS disorders in mammals other than humans.

The invention also encompasses the use of the provided compounds ascysteine, cysteine and/or glutathione supplements that can beadministered to healthy subjects and/or subjects suffering from a CNSdisorder.

Thus, in one aspect, the present invention is directed to compounds ofFormula I:

where

-   R is selected from the group consisting of alkyl and aryl,    preferably from methyl and phenyl.

In another aspect, the present invention is directed to compounds ofFormula II:

where

-   R is selected from the group consisting of

In another aspect, the present invention is directed to compounds ofFormula III:

where R is selected from the group consisting of

where R₁ is alkyl, preferably methyl, or aryl, preferably, phenyl; or R₁comprises an amino acid with the carbonyl.

In another aspect, the present invention is directed to compounds ofFormula IV:

where R is selected from the group consisting of

With respect to the compounds of Formula IV, the invention alsoencompasses compounds where the trityl moiety is replaced with anotherS-protecting group, for example a thioester, such as acetyl orphenylacetyl.

Also, the invention encompasses mixed dimers of the compounds of FormulaIV, including but not limited to, the following compounds:

In another aspect, the present invention is directed to the compoundshaving the following structures:

Certain compounds described herein may contain one or more chiral atoms,or may otherwise be capable of existing as two enantiomers, or two ormore diastereoisomers.

Accordingly, the compounds of this invention include mixtures ofenantiomers/diastereoisomers as well as purifiedenantiomers/diastereoisomers or enantiomerically/diastereoisomericallyenriched mixtures.

Also included within the scope of the invention are the individualisomers of the compounds represented by formulas above as well as anywholly or partially equilibrated mixtures thereof.

The present invention also covers the individual isomers of thecompounds represented by the formulas above as mixtures with isomersthereof in which one or more chiral centers are inverted. Also, it isunderstood that all tautomers and mixtures of tautomers are includedwithin the scope of the compounds of the formulas above.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, e.g., hem i-hydrate. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water, ethanol, and the like are equivalent to the unsolvatedforms for the purposes of the invention.

Certain compounds of the invention also form pharmaceutically acceptablesalts.

The phrase “pharmaceutically acceptable salt” means those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq.

Pharmaceutically acceptable salts include, but are not limited to, acidaddition salts. For example, the nitrogen atoms may form salts withacids. Representative acid addition salts include, but are not limitedto acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid and phosphoric acid and such organic acids as oxalic acid,maleic acid, succinic acid and citric acid.

Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions can be specially formulated for oraladministration in solid or liquid form, for parenteral injection or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, transdermally (e.g. using a patch),transmucosally, sublingually, pulmonary, intraperitoneally, topically(as by powders, ointments or drops), bucally or as an oral or nasalspray. The term “parenterally,” as used herein, refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a component of the present invention and aphysiologically tolerable diluent. The present invention includes one ormore compounds as described above formulated into compositions togetherwith one or more non-toxic physiologically tolerable or acceptablediluents, carriers, adjuvants or vehicles that are collectively referredto herein as diluents, for parenteral injection, for intranasaldelivery, for oral administration in solid or liquid form, for rectal ortopical administration, among others.

Compositions suitable for parenteral injection may comprisephysiologically acceptable, sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), vegetable oils (such asolive oil), injectable organic esters such as ethyl oleate, and suitablemixtures thereof.

These compositions can also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Ophthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptableexcipients.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.0001 to about 1000mg/kg/day. If desired, the effective daily dose can be divided intomultiple doses for purposes of administration; consequently, single dosecompositions may contain such amounts or submultiples thereof to make upthe daily dose.

For a clearer understanding of the invention, details are providedbelow. These are merely illustrations and are not to be understood aslimiting the scope of the invention in any way. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art from thefollowing examples and foregoing description. Such modifications arealso intended to fall within the scope of the appended claims.

EXAMPLES Example 1 Effect of a Drug on Cystine, Cysteine and GlutathioneLevels (Prophetic)

Part 1A

The purpose of this experiment is to provide data to support theconclusion that the compounds of the invention increase the levels ofcysteine and cystine in normal systems, and in glutathione-deficientsystems also increase the levels of glutathione.

A prodrug (0-90 mg/kg, po) will be administered to rats and tissuelevels of cystine, cysteine, and glutathione in multiple regions of thebrain (at least the striatum and prefrontal cortex) will be measuredusing HPLC with electrochemical detection. This experiment will beconducted across time (0.5, 1, 2, 4, & 8 hr) to ensure that changes incystine and glutathione do not simply vary as a function of time (e.g,the glutathione effects take longer to materialize).

It is believed that the experiment will repeat earlier observations thatthe compounds increase cysteine and cystine in normal systems, and inglutathione-deficient systems also increase the levels of glutathionerelative to rats receiving vehicle without a drug.

Part 1B

The next part of the experiment will be to create a condition wherebytissue levels of glutathione are diminished to demonstrate that theelevated levels of cystine in the cell would be used to restore/maintainglutathione levels.

This can be examined in at least two ways.

First, the experiment described in part 1A is repeated, except theharvested tissue is exposed to agents that induce oxidative stress whichwould prompt the cells to use/increase the synthesis of glutathione (thedetails are provided below). Specifically, the inventors have found thatiron (0-120 min exposure to 0-100 microM) and ethacrynic acid (0-30 minexposure to 0-10 microM) decrease tissue levels of glutathione incultured cells.

The expected result from this experiment is that accumulation of cystineinside the cell will be used to maintain glutathione levels. Thus, it isexpected that the prodrug treatment conditions (dose, and pretreatmenttime prior to harvesting the tissue) that produced the peak increase intissue cystine levels in the first experiment would be the mosteffective in maintaining normal glutathione levels even in the face ofoxidative stress.

Second, the inventors have found that rats in the MAM neurodevelopmentalmodel of schizophrenia (described in detail below) express a modestreduction in tissue levels of glutathione—thus providing a second modelof impaired glutathione function that may enable testing the premisethat some prodrugs only restore glutathione levels without promotingaccumulation of glutathione under normal conditions. This approach wouldhave the added benefit of allowing assessing the impact of the compoundson cognitive changes that are thought to be relevant to schizophrenia.Thus, one would be able to test the hypothesis that the conditions thatnormalize glutathione are also conditions that are expected to improvecognitive performance. Attentional Set Shifting, which is a cognitivetask that reflects a deficit in MAM-treated rats that can be restoredusing NAC, is described in detail below.

If the expected results are obtained, this would convincinglydemonstrate the conditions needed for prodrugs to elevate levels ofglutathione. The current thinking is that the rate-limiting step inglutathione synthesis is cystine availability in the cell. The obtaineddata would advance this understanding by demonstrating the importance ofother factors, namely the depletion of glutathione.

Tissue Assay

The tissue punches (1 mm punches will be taken from either the striatumor the medial prefrontal cortex) will be homogenized in a buffersolution used to prevent the degradation of thiols. One fraction will beused to determine protein content and the other fraction will be used todetermine thiol content using HPLC with EC detection (eg, Decade II,reactor cell, −1.4V; Flex Cell +0.65V, Antec Leyden, Netherlands).

MAM

Timed pregnant Sprauge-Dawley rats are given an acute injection ofmethylazoxymethanol (MAM; 22 mg/kg, IP) or vehicle on gestational day17. Following vaginal birth, all mothers and offspring are leftundisturbed until weaning on postnatal day 22.

Attentional Set Shifting

Seven days prior to testing the animals will be food deprived to 85% oftheir free-feeding weight. Rats will be trained and tested on a four-armcross maze (60×20×12 inches), constructed from Plexiglas with aremovable arm to form a “T” configuration. On the first habituation day,the rat will be allowed to explore and consume up to 20 sugar pelletsfor 15 minutes. On the second day, the maze will be baited with 12pellets for 15 minutes. On subsequent days, only one pellet will beplaced at the end of each arm. This procedure will be continued dailyuntil the rat consumes 16 sugar pellets in 15 minutes. Once achieved,the turn bias will be determined by forming a “T” configuration with theremovable arm. A black-and-white piece of laminated paper for a visualcue will be placed on the floor in one of the arms. One pellet will beplaced in each food well of the “T” arms. The rat will then be placed inthe stem arm and allowed to choose between the two arms. Cognitiveperformance will be examined over the following three day period.

-   Day 1: Visual-cue learning: Rats will be trained to enter the “T”    maze arm containing the visual cue. Each trial began with the    placement of the rat in one of three arms. The rat will then be    permitted to enter one of the two arms and consume the sugar pellet.    The visual cue will be placed in each arm 50% of the time. Trials    will continue until 10 consecutive correct choices are made. Once    achieved, the rat will undergo a probe trial where placement begins    in the arm which was not previously used. A correct choice on the    probe trial will concluded testing. An incorrect choice will result    in continued training as before, however only a criterion of five    correct trials will be required before the administration of a    subsequent probe trial.-   Day 2: Response discrimination: On the second day, animals will be    required to choose the arm in the opposite direction of their turn    bias regardless of visual cue placement. The visual cue will be    placed in each arm for an equal number of trials. All other    criterion and aspects of training will be identical to those used on    Day 1. On probe trials, the visual cue will be placed in the arm    opposite to the direction the rat was required to turn.-   Day 3: Reversal learning: For the response reversal, animals have to    turn opposite to the direction that resulted in reinforcement during    day 2.

Example 2 Synthesis of the Claimed Compounds (Prophetic)

Exemplary synthetic strategies are outlined in Schemes 1-5 which yieldprocysteine-like compounds according to the present invention.

No representation has been made that the actual synthesis has beenperformed. However, it is believed that a person of skill in the artwould know how to synthesize the claimed compounds based, in part, onthe provided Schemes 1-5.

R is selected from the group consisting of alkyl (preferably, methyl)and aryl (preferably, phenyl).

Description of Reactions in Scheme 1

Transformation of L-2-oxo-4-thiazolidinecarboxylic acid to(4R)-2-ethoxy-4,5-dihydro-thiazole-4-carboxylic acid using oxygenalkylating conditions can be achieved by multiple protocols by thoseskilled in the art. One such example is the application oftriethyloxonium tetrafluoroborate in a suitable solvent, such asdichloromethane, potentially in the presence of a base, such as cesiumcarbonate. Alternatively, protection of the acid with a labile group,such as its allyl or 2-trimethylsilylethyl ester, followed by theapplication of oxygen alkylating conditions, such as usingtriethyloxonium tetrafluoroborate, followed by chemoselective cleavageof the ester, such as with palladium or fluoride respectively, willgenerate (4R)-2-ethoxy-4,5-dihydro-thiazole-4-carboxylic acid. Anotherapproach uses L-cysteine, its salt or its suitably protected ester incontact with tetraethyl orthocarbonate in the presence of a mild base,such as sodium acetate, at elevated temperatures, such as 80 to 100° C.,followed by chemoselective removal of the ester or protonation of thecarboxylic acid will also generate(4R)-2-ethoxy-4,5-dihydro-thiazole-4-carboxylic acid. Conversion of the(4R)-2-ethoxy-4,5-dihydro-thiazole-4-carboxylic acid into alternatealkyloxy derivatives, for example benzyl, can be accomplished by heatingin the presence of excess of the appropriate alcohol, such as benzylalcohol.

R is chosen from alkyl, aryl, or heteroaryl or together with thecarbonyl it can comprise an amino acid.

Description of Reactions in Scheme 2

Using literature protocols, such as lannotta, Daniela et al, TetrahedronLetters, 2010, 51 4558-4559, or a related approach,L-thiazolidine-4-carboxylic acid is converted to the symmetricaldiketopiperazine of cysteine. Acylation of the free thiols can beaccomplished with, for example, acetyl chloride (R=methyl) or benzoylchloride (R=phenyl), in the presence of a base, such as triethylamine,in a suitable solvent. Formation of theS,S-di-tert-butyldiketopiperazine of L-cysteine can be accomplished byself coupling of two molecules of S-tert-butyl-Lcysteine facilitated bya coupling agent, such as2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate, in the presence of a base, such as triethylamine,in a suitable solvent, such as DMF. Alternatively, coupling ofdifferentially functionalized S-tert-butyl-L-cysteine, for example witha methyl ester and Fmoc, using a peptide coupling agent, such as2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate, in the presence of a base, such as triethylamine,in a suitable solvent, such as THF, forms the pre-cyclizeddi-S,S-di-tert-butyl-L-cysteine dipeptide. Liberation of the N-terminusamine, for example by removal of the Fmoc group with piperidine,followed by subjecting a solution of the resulting primary amine toelevated temperatures will result in diketopiperzine formationgenerating the symmetrical S,S-di-tert-butyl diketopiperazine ofL-cysteine.

R′ is a readily cleavable ester, including but not limited to allyl.

Description of Reactions in Scheme 3A

L-2-Oxo-4-thiazolidinecarboxylic acid can be converted to an activatedester, with for example bis(2-oxo-3-oxazolidinyl)phosphonic chloride inthe presence of a base like triethylamine, and contacted withN-acetyl-L-cysteine or its ester, such as the allyl, in the presence ofa base, such as triethylamine, generating the thioester. If theN-acetyl-L-cysteine is utilized protonation will generate acid2-acetylamino-3-(2-oxo-thiazolidine-4-carbonylsulfanyl)-propionic acid,while if an ester of N-acetyl-L-cysteine is employed its cleavage, suchas with palladium (0) for the allyl ester, will generate the compound2-acetylamino-3-(2-oxo-thiazolidine-4-carbonylsulfanyl)-propionic acid.The activate ester generated by contactingL-2-oxo-4-thiazolidinecarboxylic acid with an activating agent, such asbis(2-oxo-3-oxazolidinyl)phosphonic chloride in the presence of a baselike triethylamine, can be contacted with sarcosine to generate[methyl-((4R)-2-oxo-thiazolidine-4-carbonyl)-amino]-acetic acid.Numerous alternate methods to activate L-2-oxo-4-thiazolidinecarboxylicacid for coupling to generate its corresponding thioester or amide canbe envisioned by those skilled in the art, one such non-exclusiveexample is by generating its benzotriazole utilizing thionyl chloride inan analogous manner to that detailed by Alan R. Katritzky and coworkersin The Journal of Organic Chemistry (2011), volume 76, page 85-96.

Description of Reactions in Scheme 3B

S-Trityl-N-acetyl-L-cysteine and t-butyl ester of N-methylglycine in thepresence of a coupling agent, such as2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate, in the presence of a base, such as triethylamine,in a suitable solvent, such as DMF, will generate the correspondingdipeptide. Removal of the tert-butyl ester and trityl group with acidicconditions, such as contact with trifluoroacetic acid in the presence oftriethylsilane, generate the penultimate intermediate. Cyclizationoccurs by activation of the acid, such as by 2,2′-dipyridyldisulfide andtriphenylphosphine (see, for example, U.S. Pat. No. 4,287,203) ordicyclohexylcarbodiimide (see, Ura, Yasuyuki et al, Organic andBiomolecular Chemistry; vol. 7; nb. 14; (2009); p. 2878-2884), in anappropriate solvent, such as toluene or dichloromethane, generatingN-(4-methyl-2,5-dioxo-[1,4]thiazepan-6-yl)-acetamide.

Description of Reactions in Scheme 4

Cysteine, in contact with an acid, such as trifuoroacetic acid or borontrifluoride, and trityl alcohol or 9-phenyl-9-fluorenol, produces theS-trityl or S-(9-phenylfluoren-9-yl) cysteine, respectively (see, Wolfe,Saul et al, Canadian Journal of Chemistry, 1981, 59, 460-421 andZee-Cheng, K.-Y. et al, Journal of Medicinal Chemistry 1970, 13,414-418). Contact of the resulting S-trityl or S-(9-phenylfluoren-9-yl)cysteine with phenylacetic acid derivative, such as its anhydride oracid chloride, in the presence of a base, such as triethylamine,produces the corresponding phenylacetamide product. Alternatively, thephenylacetamide of cysteine can be generated by coupling the amine withan activated form of phenylacetic acid, such as it anhydride or acidchloride or acid with peptide coupling agent, in the presence of a base,such as triethylamine. The phenylacetamide of cysteine can beS-functionalized by contact with an acid, such as trifuoroacetic acid orboron trifluoride, and trityl alcohol or 9-phenyl-9-fluorenol producingthe S-trityl or S-(9-phenylfluoren-9-yl) version of phenylacetamide ofcysteine, respectively.

Description of Reaction in Scheme 5

Treatment of L-2-oxo-4-thiazolidinecarboxylic acid analogously to theprocess described in Seki, Masahiko et al, Chemistry—A European Journal,2004, vol. 10, p. 6102-6110 with a base, such as sodium hydroxide, in asuitable solvent, such as DMSO, in the presence of an ethylating agent,such as ethyl iodide will generate(4R)-3-ethyl-2-oxo-thiazolidine-4-carboxylic acid (N39).

Example 3 Synthesis of Mixed Dimers of Compounds of FormulaIV(Prophetic)

Exemplary synthetic strategies are outlined below which yield mixeddimers of compounds of Formula IV according to the present invention.

No representation has been made that the actual synthesis has beenperformed. However, it is believed that a person of skill in the artwould know how to synthesize these compounds based, in part, on theprovided synthetic strategies.

R is preferably H,

Reaction of cystine with one equivalent of an acylating agent, forexample, phenylacetic anhydride, followed by reaction of the primaryamine with the appropriate agent containing a leaving group, L, willgenerate the desired mixed dimer, or the ammonium salt in the case ofR═H.

R is preferably H

or benzyl-CO.

Incorporation of the appropriate R group onto ethyl cysteine willgenerate the appropriately functionalized ethyl cysteine. Activation ofthe sulfur for dimer formation by incorporation of a leaving group isthen performed. One method as a non-exclusive example is to apply theprotocol by Orrillo, A. Gaston et al, Chemical Communications, 2008, 42,5298-5300, where L is S(CH₂)₄CH_(3.) Reaction of the activated sulfurwith the methyl ester of phenylacetamide or cysteine in the presence ofa base, such as triethylamine will generate the mixed dimer as itsdiester. Selective removal of the methyl ester using saponificationprotocols known to those skilled in the art, such as lithium hydroxidein a dioxane-water mixture, generates the mono ethyl ester of the dimer.Removal of the ethyl ester by saponification conditions known to thoseskilled in the art, such as sodium hydroxide in ethanol-water mixture,generates the mixed dimer of cysteine with different N-substitutions.

R is preferably H,

Incorporation of the phenylacetyl group onto the nitrogen of ethylcysteine, such as by contacting with phenylacetic anhydride, generatesthe phenylacetamide version of ethyl cysteine. Activation of the sulfurfor dimer formation by incorporation of a leaving group is thenperformed. One method as a non-exclusive example is to apply theprotocol by Orrillo, A. Gaston et al, Chemical Communications, 2008, 42,5298-5300, where L is S(CH₂)₄CH₃. Reaction of the actived sulfur withthe ethyl ester of the appropriately substituted cysteine in thepresence of a base, such as triethylamine, will generate the diethylester of the mixed dimer. Removal of the ethyl esters by saponificationconditions known to those skilled in the art, such as sodium hydroxidein ethanol-water mixture, generates the mixed dimer of cysteine withdifferent N-substitutions.

1. A method of treating a disease or condition of the Central NervousSystem (CNS) selected from the group consisting of schizophrenia, drugcraving, drug addiction, bipolar disorder, anxiety, depression,Parkinson's disease, Alzheimer's disease, cognitive dysfunction,multiple sclerosis, Amyotrophic lateral sclerosis (ALS), ischemicstroke, HIV dementia, and Huntington's disease comprising administeringto a subject in need thereof a therapeutically effective amount of acompound of the following formula


2. A method of treating schizophrenia comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof the following formula


3. A method of treating Parkinson's disease comprising administering toa subject in need thereof a therapeutically effective amount of acompound of the following formula